scholarly journals Acute effects of the imidacloprid metabolite desnitro-imidacloprid on human nACh receptors relevant for neuronal signaling

2021 ◽  
Author(s):  
Dominik Loser ◽  
Karin Grillberger ◽  
Maria G. Hinojosa ◽  
Jonathan Blum ◽  
Yves Haufe ◽  
...  
Keyword(s):  
Dietary Exposure ◽  
High Sensitivity ◽  
Docking Studies ◽  
Receptor Subtypes ◽  
Receptor Models ◽  
Human Neurons ◽  
Similar Range ◽  
Transmembrane Currents ◽  
Α7 Nachrs ◽  
Agonistic Effect

AbstractSeveral neonicotinoids have recently been shown to activate the nicotinic acetylcholine receptor (nAChR) on human neurons. Moreover, imidacloprid (IMI) and other members of this pesticide family form a set of diverse metabolites within crops. Among these, desnitro-imidacloprid (DN-IMI) is of special toxicological interest, as there is evidence (i) for human dietary exposure to this metabolite, (ii) and that DN-IMI is a strong trigger of mammalian nicotinic responses. We set out here to quantify responses of human nAChRs to DN-IMI and an alternative metabolite, IMI-olefin. To evaluate toxicological hazards, these data were then compared to those of IMI and nicotine. Ca2+-imaging experiments on human neurons showed that DN-IMI exhibits an agonistic effect on nAChRs at sub-micromolar concentrations (equipotent with nicotine) while IMI-olefin activated the receptors less potently (in a similar range as IMI). Direct experimental data on the interaction with defined receptor subtypes were obtained by heterologous expression of various human nAChR subtypes in Xenopus laevis oocytes and measurement of the transmembrane currents evoked by exposure to putative ligands. DN-IMI acted on the physiologically important human nAChR subtypes α7, α3β4, and α4β2 (high-sensitivity variant) with similar potency as nicotine. IMI and IMI-olefin were confirmed as nAChR agonists, although with 2–3 orders of magnitude lower potency. Molecular docking studies, using receptor models for the α7 and α4β2 nAChR subtypes supported an activity of DN-IMI similar to that of nicotine. In summary, these data suggest that DN-IMI functionally affects human neurons similar to the well-established neurotoxicant nicotine by triggering α7 and several non-α7 nAChRs.

scholarly journals Discovery of benzothiazolylquinoline conjugates as novel human A 3 receptor antagonists: biological evaluations and molecular docking studies

2018 ◽  
Vol 5 (2) ◽  
pp. 171622 ◽  
Author(s):  
Bidisha Sarkar ◽  
Santanu Maiti ◽  
Gajanan Raosaheb Jadhav ◽  
Priyankar Paira
Keyword(s):  
Molecular Docking ◽  
Cell Lines ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Radioligand Binding ◽  
Physiological Responses ◽  
Docking Studies ◽  
Receptor Subtypes ◽  
Binding Data ◽  
Major Interest

Adenosine is known as an endogenous purine nucleoside and it modulates a wide variety of physiological responses by interacting with adenosine receptors. Among the four adenosine receptor subtypes, the A 3 receptor is of major interest in this study as it is overexpressed in some cancer cell lines. Herein, we have highlighted the strategy of designing the h A 3 receptor targeted novel benzothiazolylquinoline scaffolds. The radioligand binding data of the reported compounds are rationalized with the molecular docking results. Compound 6a showed best potency and selectivity at h A 3 among other adenosine receptors.

scholarly journals Arsenic Concentrations and Dietary Exposure in Rice-Based Infant Food in Australia

2020 ◽  
Vol 17 (2) ◽  
pp. 415
Author(s):  
Zhuyun Gu ◽  
Shamali de Silva ◽  
Suzie M. Reichman
Keyword(s):  
Hydride Generation ◽  
Inorganic Arsenic ◽  
Dietary Exposure ◽  
High Sensitivity ◽  
Infants And Children ◽  
Infant Food ◽  
Acid Extraction ◽  
Limited Information ◽  
Icp Ms ◽  
Increased Risk

Rice-based products are widely used to feed infants and young children. However, the association of rice-based products and high arsenic (As) concentrations have been investigated in a number of studies, but there is limited information from Australia. Therefore, the purpose of this study was to determine the As concentration and dietary exposure in infant rice milk, cereal, crackers and pasta as well as to investigate the relationship between As concentration and rice content, rice type and product origin. Total arsenic (tAs) concentrations were determined by nitric acid digestion and ICP-MS while inorganic arsenic (iAs) was determined by acid extraction, followed by ICP-MS with an interfaced hydride generation system. Nearly 75% of samples had inorganic As exceeding the EU maximum levels for infants and children (0.1 mg kg−1) and the mean iAs percentage of total reached as high as 84.8%. High tAs concentration was positively correlated with rice content and also related to brown (wholegrain). Estimates of dietary exposure showed that infants consuming large amounts of rice pasta or crackers will have an increased risk of health impact associated with excess intake of As through dietary exposure. Moreover, the current Australian guidelines for As in rice (1 mg kg−1) are above the WHO or EU guideline and therefore, will be less protective of high sensitivity consumers like infants and children.

Differential distribution of excitatory amino acid receptors on embryonic rat spinal cord neurons in culture

1991 ◽  
Vol 65 (4) ◽  
pp. 899-913 ◽  
Author(s):  
O. Arancio ◽  
A. B. MacDermott
Keyword(s):  
Spinal Cord ◽  
Amino Acid ◽  
Excitatory Amino Acid ◽  
High Sensitivity ◽  
Receptor Subtypes ◽  
Rat Spinal Cord ◽  
Differential Distribution ◽  
Spinal Cord Neurons ◽  
Current Loss ◽  
High K

1. Excitatory amino acid (EAA) receptors mediate synaptic transmission in many areas of the vertebrate CNS. To map the distribution of the EAA receptors, three agonists selective for EAA receptor subtypes [kainate, quisqualate, and N-methyl-D-aspartate (NMDA)] were applied by pressure to the cell bodies and neurites of voltage-clamped, embryonic rat spinal cord neurons in culture. 2. Current loss along the neurite between the site of activation and the recording electrode at the soma was estimated independently of variations in receptor density by focal application of high [K+] solution. This estimate was used to compensate agonist-evoked responses for current loss due to leak. K(+)-evoked current amplitudes progressively decreased as applications were made at more distal positions along the neurite. 3. Response amplitudes to EAAs showed a monotonic decay, similar to that with high [K+] solution, in only a few of the cells tested with each agonist. The majority of neurons had areas of high agonist sensitivity along the neurites, implying a nonuniform density of receptors. Such regions sometimes occurred at the most proximal segment of the neurite. Most neurites had distal regions of agonist sensitivity that ranged from 40 to 300% higher than at the soma. 4. The relative distributions of the three EAA receptors were compared by applying two agonists to the same sites along neurites and observing variations in normalized response amplitudes. When comparing NMDA versus non-NMDA receptor distributions on the same neurite, approximately 40% of the cells had similar patterns to two agonists, and the remaining 60% had different patterns. When sensitivity to the two non-NMDA agonists kainate and quisqualate were compared, about one-half of the cells tested had different patterns of agonist sensitivity. 5. Areas of high sensitivity persisted after block of calcium channels by addition of La3+ to the bath solution and after prevention of evoked transmitter release by a low [Ca2+]/high [Mg2+] solution. 6. These results show that spinal cord neurons can have regions of high agonist sensitivity to NMDA, kainate, and quisqualate along their neurites and that the sensitivity to any one of the EAA receptor subtypes can be elevated independently of the others.

scholarly journals Molecular determinants underlying DS2 activity at δ-containing GABAA receptors

2021 ◽  
Author(s):  
Christina B. Falk-Petersen ◽  
Frederik Rostrup ◽  
Rebekka Löffler ◽  
Stine Buchleithner ◽  
Kasper Harpsøe ◽  
...  
Keyword(s):  
Binding Site ◽  
Drug Targets ◽  
Transmembrane Domain ◽  
Direct Interaction ◽  
Binding Pocket ◽  
Docking Studies ◽  
Tonic Inhibition ◽  
Site Directed Mutagenesis ◽  
Receptor Subtypes ◽  
Molecular Determinants

AbstractDelta selective compound 2 (DS2) is one of the most widely used tools to study selective actions mediated by δ subunit-containing GABAA receptors. DS2 was discovered over 10 years ago, but despite great efforts, the precise molecular site of action has remained elusive.Using a combination of computational modeling, site-directed mutagenesis and cell-based pharmacological assays, we probed three potential binding sites for DS2 and analogs at α4β1δ receptors: an α4(+)δ(-) interface site in the extracellular domain (ECD), equivalent to the diazepam binding site in αβγ2 receptors, and two sites in the transmembrane domain (TMD); one in the α4(+)β1(-) and one in the α4(-)β1(+) interface, with the α4(-)β1(+) site corresponding to the binding site for etomidate and a recently disclosed low-affinity binding site for diazepam. We show that mutations in the ECD site did not abrogate DS2 modulation. However, mutations in the TMD α4(+)β1(-) interface, either α4(S303L) of the α4(+)-side or β1(I289Q) of the β1(-)-side, convincingly disrupted the positive allosteric modulation by DS2. This was consistently demonstrated both in an assay measuring membrane potential changes and by whole-cell patchclamp electrophysiology and rationalized by docking studies. Importantly, general sensitivity to modulators was not compromised in the mutated receptors. This study sheds important light on the long-sought molecular recognition site for DS2, refutes the misconception that the selectivity of DS2 for δ-containing receptors is caused by a direct interaction with the δ-subunit, and instead points towards a functional selectivity of DS2 and its analogs via a surprisingly well-conserved binding pocket in the TMD.Significance statementδ-Containing GABAA receptors represent potential drug targets for the treatment of several neurological conditions with aberrant tonic inhibition. Yet, no drugs are currently in clinical use. With the identification of the molecular determinants responsible for positive modulation by the know compound DS2, the ground is laid for design of ligands that selectively target δ-containing GABAA receptor subtypes, for better understanding of tonic inhibition, and, ultimately, for rational development of novel drugs.

scholarly journals Time and space-resolved quantification of plasma membrane sialylation for measurements of cell function and neurotoxicity

2019 ◽  
Vol 94 (2) ◽  
pp. 449-467 ◽  
Author(s):  
Petra Kranaster ◽  
Christiaan Karreman ◽  
Jeremias E. G. A. Dold ◽  
Alice Krebs ◽  
Melina Funke ◽  
...  
Keyword(s):  
Cell Function ◽  
High Sensitivity ◽  
Cell Labeling ◽  
Time Resolved ◽  
Glycoprotein Synthesis ◽  
Human Neurons ◽  
Toxicological Studies ◽  
Label Incorporation ◽  
Respiration Inhibitors ◽  
Live Cell Labeling

AbstractWhile there are many methods to quantify the synthesis, localization, and pool sizes of proteins and DNA during physiological responses and toxicological stress, only few approaches allow following the fate of carbohydrates. One of them is metabolic glycoengineering (MGE), which makes use of chemically modified sugars (CMS) that enter the cellular biosynthesis pathways leading to glycoproteins and glycolipids. The CMS can subsequently be coupled (via bio-orthogonal chemical reactions) to tags that are quantifiable by microscopic imaging. We asked here, whether MGE can be used in a quantitative and time-resolved way to study neuronal glycoprotein synthesis and its impairment. We focused on the detection of sialic acid (Sia), by feeding human neurons the biosynthetic precursor N-acetyl-mannosamine, modified by an azide tag. Using this system, we identified non-toxic conditions that allowed live cell labeling with high spatial and temporal resolution, as well as the quantification of cell surface Sia. Using combinations of immunostaining, chromatography, and western blotting, we quantified the percentage of cellular label incorporation and effects on glycoproteins such as polysialylated neural cell adhesion molecule. A specific imaging algorithm was used to quantify Sia incorporation into neuronal projections, as potential measure of complex cell function in toxicological studies. When various toxicants were studied, we identified a subgroup (mitochondrial respiration inhibitors) that affected neurite glycan levels several hours before any other viability parameter was affected. The MGE-based neurotoxicity assay, thus allowed the identification of subtle impairments of neurochemical function with very high sensitivity.

Radio Measurements of Coronal Magnetic Fields

1994 ◽  
Vol 144 ◽  
pp. 21-28 ◽  
Author(s):  
G. B. Gelfreikh
Keyword(s):  
Magnetic Field ◽  
Magnetic Fields ◽  
Solar Corona ◽  
Active Regions ◽  
High Sensitivity ◽  
Coronal Magnetic Field ◽  
Transverse Magnetic ◽  
Radio Sources ◽  
Radio Waves ◽  
Solar Active Regions

AbstractA review of methods of measuring magnetic fields in the solar corona using spectral-polarization observations at microwaves with high spatial resolution is presented. The methods are based on the theory of thermal bremsstrahlung, thermal cyclotron emission, propagation of radio waves in quasi-transverse magnetic field and Faraday rotation of the plane of polarization. The most explicit program of measurements of magnetic fields in the atmosphere of solar active regions has been carried out using radio observations performed on the large reflector radio telescope of the Russian Academy of Sciences — RATAN-600. This proved possible due to good wavelength coverage, multichannel spectrographs observations and high sensitivity to polarization of the instrument. Besides direct measurements of the strength of the magnetic fields in some cases the peculiar parameters of radio sources, such as very steep spectra and high brightness temperatures provide some information on a very complicated local structure of the coronal magnetic field. Of special interest are the results found from combined RATAN-600 and large antennas of aperture synthesis (VLA and WSRT), the latter giving more detailed information on twodimensional structure of radio sources. The bulk of the data obtained allows us to investigate themagnetospheresof the solar active regions as the space in the solar corona where the structures and physical processes are controlled both by the photospheric/underphotospheric currents and surrounding “quiet” corona.

Backscattered Electron Imaging of GaAs/AlGaAs Super Lattice Structures with an Ultra-High- Resolution SEM

1988 ◽  
Vol 46 ◽  
pp. 204-205
Author(s):  
Kazumichi Ogura ◽  
Michael M. Kersker
Keyword(s):  
High Resolution ◽  
Layer Structure ◽  
High Sensitivity ◽  
Beam Current ◽  
Electron Beam Current ◽  
Lattice Structures ◽  
Super Lattice ◽  
Different Types ◽  
Backscattered Electron ◽  
Electron Imaging

Backscattered electron (BE) images of GaAs/AlGaAs super lattice structures were observed with an ultra high resolution (UHR) SEM JSM-890 with an ultra high sensitivity BE detector. Three different types of super lattice structures of GaAs/AlGaAs were examined. Each GaAs/AlGaAs wafer was cleaved by a razor after it was heated for approximately 1 minute and its crosssectional plane was observed.First, a multi-layer structure of GaAs (100nm)/AlGaAs (lOOnm) where A1 content was successively changed from 0.4 to 0.03 was observed. Figures 1 (a) and (b) are BE images taken at an accelerating voltage of 15kV with an electron beam current of 20pA. Figure 1 (c) is a sketch of this multi-layer structure corresponding to the BE images. The various layers are clearly observed. The differences in A1 content between A1 0.35 Ga 0.65 As, A1 0.4 Ga 0.6 As, and A1 0.31 Ga 0.69 As were clearly observed in the contrast of the BE image.

An x-ray microprobe based upon a close-coupled focal-spot / glass capillary arrangement

1992 ◽  
Vol 50 (2) ◽  
pp. 1758-1759
Author(s):  
D. A. Carpenter ◽  
M. A. Taylor
Keyword(s):  
Imaging Techniques ◽  
Fluorescence Analysis ◽  
High Sensitivity ◽  
Specimen Preparation ◽  
X Rays ◽  
Glass Capillary ◽  
Close Coupling ◽  
X Ray ◽  
Point To Point ◽  
Beam Damage

The development of intense sources of x rays has led to renewed interest in the use of microbeams of x rays in x-ray fluorescence analysis. Sparks pointed out that the use of x rays as a probe offered the advantages of high sensitivity, low detection limits, low beam damage, and large penetration depths with minimal specimen preparation or perturbation. In addition, the option of air operation provided special advantages for examination of hydrated systems or for nondestructive microanalysis of large specimens.The disadvantages of synchrotron sources prompted the development of laboratory-based instrumentation with various schemes to maximize the beam flux while maintaining small point-to-point resolution. Nichols and Ryon developed a microprobe using a rotating anode source and a modified microdiffractometer. Cross and Wherry showed that by close-coupling the x-ray source, specimen, and detector, good intensities could be obtained for beam sizes between 30 and 100μm. More importantly, both groups combined specimen scanning with modern imaging techniques for rapid element mapping.

Ultrastructural identification of three types of sensory setae on copepod antennae

1995 ◽  
Vol 53 ◽  
pp. 956-957
Author(s):  
T. M. Weatherby ◽  
P.H. Lenz
Keyword(s):  
Phase Locking ◽  
Membrane Surface ◽  
Reaction Times ◽  
High Sensitivity ◽  
Structural Features ◽  
Calanoid Copepods ◽  
Marine Food Webs ◽  
Dendritic Membrane ◽  
Ultrastructural Characterization

Crustaceans, as well as other arthropods, are covered with sensory setae and hairs, including mechanoand chemosensory sensillae with a ciliary origin. Calanoid copepods are small planktonic crustaceans forming a major link in marine food webs. In conjunction with behavioral and physiological studies of the antennae of calanoids, we undertook the ultrastructural characterization of sensory setae on the antennae of Pleuromamma xiphias.Distal mechanoreceptive setae exhibit exceptional behavioral and physiological performance characteristics: high sensitivity (<10 nm displacements), fast reaction times (<1 msec latency) and phase locking to high frequencies (1-2 kHz). Unusual structural features of the mechanoreceptors are likely to be related to their physiological sensitivity. These features include a large number (up to 3000) of microtubules in each sensory cell dendrite, arising from or anchored to electron dense rods associated with the ciliary basal body microtubule doublets. The microtubules are arranged in a regular array, with bridges between and within rows. These bundles of microtubules extend far into each mechanoreceptive seta and terminate in a staggered fashion along the dendritic membrane, contacting a large membrane surface area and providing a large potential site of mechanotransduction.

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